Principal Investigator: Professor George Kirov

1a: Deletions and duplications of large stretches of chromosomes, known as copy number variants (CNVs), cause several neurodevelopmental disorders, such as schizophrenia, developmental delay and autism spectrum disorder. However, the full clinical spectrum associated with most of these CNVs has not yet been established and there is limited evidence of the impact of these CNVs in the general population, e.g. in apparently healthy carriers. We propose to identify the carriers of pathogenic CNVs in the full UK Biobank sample. We will then identify the cognitive deficits and common medical problems that are increased in carriers of each of these CNVs.

1b: The rarity of most pathogenic CNVs has so far prevented researchers from confidently establishing their full medical and neurocognitive consequences. Therefore it is currently impossible for genetic counsellors to give accurate advice to CNV carriers. Our research will provide the most comprehensive assessment of neuropsychiatric and common medical problems associated with known pathogenic CNVs. This will result in a greater understanding of the risks conferred by these CNVs for the development of diseases, and give clinicians the necessary information for diagnosing, counselling and treating the carriers of these CNVs.

1c: We will first generate a set of high quality CNVs from all participants in the UK Biobank cohort using the data from microarray genotyping already conducted by Affymetrix. (If UK Biobank calls the CNVs centrally, we can use these calls and just apply our quality control filtering). We will identify the individuals carrying pathogenic CNVs. Carriers of pathogenic CNVs will then be compared with the remaining participants, who are free of such CNVs, for neuropsychiatric problems (including cognitive performance), common medical conditions, and basic characteristics (e.g. weight and height), which can be affected by CNVs.

1d: We require genetic data from the full UK Biobank cohort. We also need a set of basic demographic and common health outcomes that could be affected by CNVs. These include neuropsychiatric outcomes such as epilepsy, psychosis, mood disorders, cognitive tests, educational indices, and self-reported medical/psychiatric conditions. When it becomes available, we would like to add the diagnostic codes from the primary care data, to supplement the self-reports. Carriers of these CNVs might have an increased rate of premature terminations and have fewer children, therefore we also want to collect the self-reported information on these outcomes.

Project Extension:

Epilepsy GWAS

I would like to use the current and forthcoming genotype data to perform a genome wide association study. Epilepsy is a common disorder and there are an estimated 4200 people with epilepsy in the UK Biobank. One method of looking for the influence of common variants in the cause of disease is with a genome wide association study (GWAS). This method is established in the study of genetic disease and relies upon comparing cases with controls. Cases are matched by certain factors such as ethnicity, and mechanism for producing the genotype, with the controls. The UK Biobank data is ideally suited to this type of analysis and has been used by many groups already for this type of analysis.

The current largest meta-analysis of GWAS for epilepsy (ILAE, Lancet Neurology 2014) had 8696 cases and 26157 controls. This yielded statistically significant loci at 2q24, 4p15.1 and 2p16.1. It is our ambition to replicate these findings and then collaborate with the ILAE consortium as they perform a mega-analysis in 2016.

We expect that this approach will lead to a number of new genome-wide loci being identified. This may directly lead to a better understanding of the biology underpinning the epilepsies.

We would not require access to any further datasets. We would use the currently available data and the second round of genotyping data when it becomes available. We will use the phenotype and drug data as it stands to refine our case definition and to exclude cases where it is likely that they have an acquired cause for their epilepsy (such as traumatic brain injury or brain tumour).

Epilepsy and common mitochondrial variation

I would like to use the current and forthcoming genotype data to look at the role of common variation in mitochondrial genes in the epilepsies. I have been in discussion with Professor Patrick Chinnery (Cambridge) about how best to test the hypothesis that the mitochondrial genome contributes to epilepsy susceptibility in people with common epilepsies. The role of mitochondrial mutation is established as a cause of MELAS and MERFF which both have epileptic seizures as a core part of their phenotype.

The mitochondrial genome is only 16569 base pairs in length and it contains 37 known genes. Our analysis would be limited to this genome initially as we look to compare common variations across the mitochondrial genome that occur more commonly in cases (people with epilepsy) than they do in people without epilepsy (our control population). Previous analyses have been beset by the lack of suitable control databases and so defining what is truly a SNP has been difficult. The MitoKor series from the Broad for example has only 435 sequences of European ancestry. The Uk Biobank offers the opportunity to overcome this power issue.

It is possible to also look at the role of nuclear encoded mitochondrial genes. One such method is the Meta-Analysis Gene-set Enrichment of variaNT Associations (MAGENTA).

The identification of a role of the mitochondrial genome in the pathophysiology of epilepsy would allow the research community to design trials for treating these epilepsies. As above, we would not require access to any further datasets. We would use the currently available data and the second round of genotyping data when it becomes available. We will use the phenotype and drug data as it stands to refine our case definition and to exclude cases where it is likely that they have an acquired cause for their epilepsy (such as traumatic brain injury or brain tumour).